由美國科學(xué)家完成的一項關(guān)鍵研究發(fā)現(xiàn)，參與催化反應(yīng)的酶經(jīng)過詳細(xì)的構(gòu)象變化,，從而完成其生物學(xué)功能，該發(fā)現(xiàn)向傳統(tǒng)藥物合成途徑的假想提出了挑戰(zhàn),，并可能幫助未來的藥物設(shè)計,。傳統(tǒng)認(rèn)為,，酶是主要以其生命存在來催化化學(xué)反應(yīng)的生物學(xué)分子,，酶催化作用傳統(tǒng)模式將被這些發(fā)現(xiàn)重寫,，另外,，該發(fā)現(xiàn)也對當(dāng)前用于藥品制造的抑制劑或工業(yè)應(yīng)用的新穎酶催化劑的理性設(shè)計提出質(zhì)疑,。美國斯克利普斯研究院的科學(xué)家證明，酶動力學(xué)構(gòu)象波動引導(dǎo)其完成自身的反應(yīng)周期,，蛋白質(zhì)的熱能運(yùn)動被用來執(zhí)行催化作用,。
研究者使用核磁共振儀研究了大腸桿菌二氫葉酸還原酶(DHFR)高能激發(fā)態(tài)，結(jié)果表明在催化周期的各個階段,，前述酶以及下面提到的酶的激發(fā)態(tài)構(gòu)象與基態(tài)構(gòu)象類似。這樣,，基態(tài)和激發(fā)態(tài)之間的動力學(xué)波動使酶達(dá)到臨近的中間狀態(tài)構(gòu)象，從而通過幫助配體與酶的結(jié)合或分開而更易于催化作用的進(jìn)行,。
美國斯克利普斯研究院分子生物學(xué)系（Scripps Research Department of Molecular Biology）的主席、美國斯克利普斯研究院Skaggs生物化學(xué)研究所（Skaggs Institute for Chemical Biology at Scripps Research）的成員Peter Wright說：“蛋白質(zhì)固有的運(yùn)動對它們生物學(xué)功能是必要的,，目前對這一點(diǎn)的認(rèn)知越來越多。這些新發(fā)現(xiàn)與傳統(tǒng)的‘誘導(dǎo)模式’假說對照,，假說的一種原則認(rèn)為配體的結(jié)合導(dǎo)致酶構(gòu)象的變化從而增加了配體與酶之間的偶聯(lián),。”
在過去多年,，制藥業(yè)都按照該假說執(zhí)行，認(rèn)為大部分酶都是天生可以自由變形的,，然而，對蛋白質(zhì)與催化功能波動偶聯(lián)的機(jī)理的了解卻非常少,。
新構(gòu)象模型被期望能對酶的偶聯(lián)作用有更深入的認(rèn)識,，并引導(dǎo)制藥業(yè)向更高戰(zhàn)略性途徑發(fā)展。“我們的研究適用廣闊的催化周期的各個環(huán)節(jié),，”Wright說,，“結(jié)果意味著對DHFR酶循環(huán)的任一中間物來說,，最低能量激發(fā)態(tài)都是機(jī)能最相關(guān)的構(gòu)象”,。
酶以一個首選的基態(tài)構(gòu)象與配體適應(yīng)性結(jié)合,，但也采取其他相關(guān)高能構(gòu)象,，以保證它能快速前進(jìn)到下一個催化步驟,。當(dāng)配體改變后,，酶的易接近的能量狀態(tài)也相應(yīng)改變，因此,，這種動態(tài)的能量勢壘能有效地為酶提供一個特殊的動力學(xué)途徑,，在此途徑中連續(xù)構(gòu)象之間的能量壘的數(shù)量和高度都是最小的,。
附：美國斯克利普斯研究院簡介
美國斯克利普斯研究院是全球規(guī)模最大的非盈利性獨(dú)立生物醫(yī)學(xué)研究機(jī)構(gòu),，它站在生物基礎(chǔ)科學(xué)的最前沿,，尋求了解最基礎(chǔ)的生命過程。斯克利普斯研究院的研究在免疫學(xué),、分子和細(xì)胞生物學(xué)、化學(xué),、神經(jīng)科學(xué)、自體免疫,，心血管,、傳染病和人造疫苗等領(lǐng)域方面得到了國際認(rèn)可,。研究院仍然保持了1961年的機(jī)構(gòu)配置，它雇用大約3,000位科學(xué)家,、博士后,、科技人員、博士學(xué)位研究生和行政與技術(shù)支持人員,?？偛吭O(shè)在加利福尼亞州拉喬拉(La Jolla)。斯克利普斯研究院佛羅里達(dá)部將研究重心集中于基本的生物醫(yī)學(xué),、藥物發(fā)現(xiàn)和技術(shù)開發(fā),。當(dāng)前科研工作臨時設(shè)在Jupiter,，2009年將永久搬到校園,。
部分英文原文：
Study Details Structural Changes of a Key Catalytic Enzyme
Scientists at The Scripps Research Institute have detailed a new hypothesis of how a key catalytic enzyme, dihydrofolate reductase (DHFR)—which is the target of several anticancer and antibiotic therapies—cycles through structural changes as it plays a critical role in promoting cell growth and proliferation.
The study was published in the September 15 (Volume 314, Issue 5793) edition of the journal Science.
Enzymes are complex proteins capable of catalyzing specific biochemical reactions in cells. While it has long been recognized that dynamic fluctuations in protein conformation or structure play a central role in enzyme catalysis, the new findings indicate that the "dynamic energy landscape" of the enzyme funnels it along a preferred pathway that actually minimizes the number and dimension of the energetic barriers to these catalytic changes.
"There is a growing awareness that the inherent motions of proteins are essential to their functions," said Peter Wright, who is chair of the Scripps Research Department of Molecular Biology and a member of the Skaggs Institute for Chemical Biology at Scripps Research. "The importance of this study is that it reveals how dynamic structural fluctuations channel an enzyme through its reaction cycle—the thermal motions of the protein are harnessed to perform its biological function, in this case, catalysis. Knowledge of the excited-state conformations of proteins may offer new opportunities for drug design."
The researchers used nuclear magnetic resonance (NMR) to detect and characterize higher energy structural sub-states (excited states) of E. coli dihydrofolate reductase, which has been used extensively as a model enzyme for investigating the relations between structure, dynamics, and function in proteins. The researchers found that, at each stage in the catalytic cycle, the excited-state conformations resembled the ground-state structures of both the preceding and the following intermediates. This means that the dynamic fluctuations between the ground state and the excited state were "priming" the enzyme to take up the conformation of the adjacent intermediate state, facilitating the progress of catalysis by aiding the movement of ligands (molecules that bind to one chemical entity to form a larger complex) on and off the enzyme.
"These findings contrast with the traditional 'induced fit' hypothesis," Wright said. "One of the tenets of that hypothesis is that the binding of ligands induces a structural change that increases the complementary relationship between the ligand and the enzyme."
更多原文鏈接：http://www.scripps.edu/news/press/091906.html
http://www.drugresearcher.com/news/ng.asp?n=70741-enzyme-dihydrofolate-reductase-catalyst
